The design and development of highly integrated, cancer-targeted nanomedicines promise to enhance disease-specific targeting and improve access to intracellular pharmacological targets. However, a detailed understanding of molecular-level interactions (e.g., modulation of cellular/subcellular functions) driving the fate of nanomedicines in biological systems remains elusive. For example, the complex interplay between endocytosis and intracellular trafficking, physiologic, and/or metabolic pathways and how the targeted nanoparticles navigate these complex systems can be important to homeostatic regulation. Moreover, this interplay can vary due to the properties of the particle probe, surrounding biological conditions, and nature of the disease itself. Furthermore, particle uptake and accumulation within specific intracellular compartments may alter functional, metabolic, and/or energy homeostasis. For example, a number of particle-based probes undergoing endocytosis and intracellular trafficking have been shown to induce autophagy and to inhibit lysosome function. However, how these effects modulate cell survival over time remains unclear.
Ultrasmall (e.g., having a diameter no greater than 20 nm, e.g., no greater than 15 nm, e.g., no greater than 10 nm) FDA-approved fluorescent organo-silica particles (C dots) that were previously surface-adapted with PET radiolabels and the integrin-targeting peptide cyclo-(Arg-Gly-Asp-Tyr) (cRGDY) were found to be a working molecular cancer imaging agent in humans. For example, C dots were shown to preferentially accumulate within αvβ3 integrin-expressing primary and/or metastatic lesions in small and larger animal and human subject melanoma models in addition to demonstrating bulk renal clearance. Detail on C dots are described in U.S. Pat. No. 8,298,677 B2 “Fluorescent silica-based nanoparticles”, U.S. Publication No. 2013/0039848 A1 “Fluorescent silica-based nanoparticles”, and U.S. Publication No. US 2014/0248210 A1 “Multimodal silica-based nanoparticles”, the contents of which are incorporated herein by reference in their entireties. Moreover, ultrasmall poly(ethylene glycol)-coated (PEGylated) near-infrared (NIR) fluorescent silica nanoparticle, referred to as C′ dots, with diameters controllable down to the sub-10 nm range that were additionally surface-modified with a 14-mer peptide analog, alpha-melanocyte stimulating hormone (α-MSH) were found to target melanocortin-1 receptors (MC1-R) expressed on malignant melanoma cells. However, it remains unknown as to how these particles may modulate cellular function and intracellular trafficking.
Thus, there remains a need to determine how variations in concentration and time-based processes influence the post-internalization fate of particle-based probes to improve the design of application-specific nanomedicine (e.g., C and C′ dot) platforms.